The epidermal growth factor receptor (EGFR) has been identified as a relevant target for treatment of solid tumors, as it is involved in regulating cellular functions important in the proliferation and survival of cancer cells. EGFR is commonly expressed in a range of tumors, and high expression is often related to poor prognosis. A new class of targeted therapies directed at inhibiting the EGFR, tyrosine kinase inhibitors, have appeared. Two known examples are gefitinib (Iressa) or erlotinib (Tarceva). Despite initial responses of some patients to these therapies, patients eventually progress by unknown mechanisms of “acquired” resistance.
EGFR has been thought to play an important role in lung cancer. However only a small portion non-small cell lung cancers (NSCLCs) respond to Iressa or Tarceva (see FIG. 1 for structures). Lung adenocarcinomas from patients who respond to the tyrosine kinase inhibitors gefitinib or erlotinib usually harbor somatic gain-of-function mutations in exons encoding the tyrosine kinase domain of EGFR. Such mutations are found in about 10% of NSCLCs from the United States [1,2,3], with higher incidences observed in east Asia [2,4,5,6]. Some 90% of NSCLC-associated mutations occur as either multi-nucleotide in-frame deletions in exon 19, involving elimination of four amino acids, Leu-Arg-Glu-Ala, or as a single nucleotide substitution at nucleotide 2573 (T→G) in exon 21, resulting in substitution of arginine for leucine at position 858 (L858R). Both of these mutations are associated with sensitivity to the small-molecule kinase inhibitors gefitinib or erlotinib [1,2,3]. Unfortunately, nearly all patients who experience marked improvement on these drugs eventually develop progression of disease. While KRAS (v-Ki-ras2, Kirsten rat sarcoma viral oncogene homolog, a RAS family member) mutations have been associated with some cases of primary resistance to gefitinib or erlotinib [7], mechanisms underlying “acquired” or “secondary” resistance are unknown.
Therefore there is a need in the art for the determining the underlying causes of such resistance so that a diagnostic test can be developed and a more effective treatment provided. Moreover, there is a need in the art for new compounds that are able to treat patients that show cancer progression or relapse despite initial response to current EGFR inhibitors.